Studies were performed to determine if patients with sickle cell disease (SCD) and age-matched children without SCD were capable of producing opsonizing activity to their infecting strains of S. pneumoniae during hospitalization for meningitis and/or bacteremia, and to determine if a rise in specific antibody titer to the infecting strains was associated with the appearance of serum opsonizing activity. Seven of the ten children without SCD and one of two children with SCD produced opsonizing activity to their infecting strains, and the other children did not. No correlation was demonstrated between production of opsonizing activity and age, length of hospitalization, type of infection, or rise in specific antibody titer. Levels and activities of the classical and alternative complement pathways were also measured in the control children and the children with SCD, and only C3 and properdin levels were reduced. Leukocyte bactericidal activity for S. aureus 502A and type 10 S. pneumoniae, serum opsonic activity for type 10 S. pneumoniae, immunoglobulin levels, and levels and activities of the alternative and classical complement pathways were measured on 18 patients with SCD during crisis. All of the patients had normal leukocyte bactericidal activity for both bacterial strains. No change in opsonic activity, immunoglobulin levels, or levels and activities of complement was observed during crisis, in comparison to when the patients were asymptomatic. Preliminary evidence was provided to suggest that reduction in opsonic activity for type 10 S. pneumoniae in uninfected patients with SCD was caused by a deficiency of antibodies.